Molecules from animals with exotic immune systems can be big business, as Andrew Joseph from STAT News points out. Pharmaceutical giant Sanofi recently bought a company focused on nanobodies, originally derived from camels, llamas and alpacas, for $4.8 billion.

Lampreys’ variable lymphocyte receptors (VLRs) are their version of antibodies, even though they look quite different in molecular terms. Research on VLRs and their origins may seem impractical. However, Cooper’s team has shown their utility as diagnostic tools, and his colleagues have been weaponizing them, possibly for use in cancer immunotherapy.

CAR-T cells have attracted attention for dramatic elimination of certain types of leukemias from the body and also for harsh side effects and staggering costs; see this opinion piece by Georgia Tech’s Aaron Levine. Now many research teams are scheming about how to apply the approach to other types of cancers. The provocative idea is: replace the standard CAR (chimeric antigen receptor) warhead with a lamprey VLR.

As described in this 2016 JCI Insight paper, Emory and University of Toronto investigators wanted to do the opposite. They were aiming to develop antibody tools for studying and manipulating plasma cells, which are the immune system’s weapons factories, where antibody production takes place. The situation is flipped when we’re talking about antibodies. Here, the goal is to stand out.

Do these guys look like good spies?

Monoclonal antibodies are classic biomedical tools (and important anticancer drugs). But it’s tricky to develop antibodies against the places where antibodies themselves are made, because of the way the immune system develops. To guard against autoimmune disease, antibodies that would react against substances in the body are often edited out.

To get around this obstacle, researchers used organisms that have very different immune systems from humans: lampreys. Emory’s Max Cooper and colleagues had already shown how lampreys have molecules — variable lymphocyte receptors or VLRs — that function like antibodies, but don’t look like them, in terms of their molecular structure.

From the paper:

We reasoned that the unique protein architecture of VLR Abs and the great evolutionary distance between lampreys and humans would allow the production of novel VLRB Abs against biomedically relevant antigens against which conventional Abs are not readily produced because of structural or tolerogenic constraints.

Cooper in Good’s laboratory in the 1960s (source: National Library of Medicine)

B cells are immune cells that display antibodies on their surfaces, and can become antibody-secreting plasma cells. Without B cells: no antibodies to protect us against bacteria and viruses. Where B cellsÂ come from, and how they can developÂ such a broad repertoire of antibody tools, was a major puzzle of 20th century immunology, which Cooper contributed toÂ solving. (See the Nature piece to learnÂ why the “B” comes from theÂ name of an organ in chickens.)

The authorsÂ did not mention that Cooper is now at Emory studying lampreys’ immune systems, which are curiouslyÂ different fromÂ those of mammals. The similarities and differences provide insights into the evolution of ourÂ immune systems. In addition, scientists here are exploring whether lamprey’s antibody-like molecules might be turned into anticancer drugs.

This complex diagram, showing the gene segments that encode lamprey variable lymphocyte receptors, comes from a recent PNAS paper published by Emory’s Max Cooper and his colleagues along with collaborators from Germany led by Thomas Boehm. Lampreys have moleculesÂ that resemble our antibodies in function, but theyÂ look very different at the protein level. The study of lamprey immunityÂ provides hints to how the vertebrate immune system has evolved.

Studying lampreys allows biologists to envision the evolutionary past, because they represent an early offshoot of the evolutionary tree, before sharks and fish. Despite their inconspicuous appearance, lampreys have a sophisticated immune system with three types of white blood cell that resemble our B and T cells, researchers have discovered.

Scientists at Emory University School of Medicine and the Max Planck Institute of Immunology and Epigenetics in Freiburg have identified a type of white blood cell in lampreys analogous to the “gamma delta T cells” found in mammals, birds and fish. Gamma delta T cells have specialized roles defending the integrity of the skin and intestines, among other functions.

The results are published in the journalÂ Nature. The finding follows anÂ earlier studyÂ showing that cells resembling two main types of white blood cells, B cells and T cells, are present in lampreys.

You can get far in biology by asking: â€œWhich came first, the chicken or the egg?â€ Max Cooper discovered the basis of modern immunology by asking basic questions.

Cooper was selected for the 2012 Deanâ€™s Distinguished Faculty Lecture and Award, and on Thursday evening dazzled an Emory University School of Medicine audience with a tour of his scientific career. He joined the Emory faculty in 2008 as a Georgia Research Alliance Eminent Scholar.

Max Cooper, MD

Cooperâ€™s research on the development of the immune system, much of it undertaken before the era of cloned genes, formed the underpinnings of medical advances ranging from bone marrow transplants to monoclonal antibodies. More recently, his research on lampreysâ€™ divergent immune systems has broadened our picture of how adaptive immunity evolved.

Cooper grew up in Mississippi and was originally trained as a pediatrician, and became interested in inherited disorders that disabled the immune system, leaving children vulnerable to infection. He joined Robert Goodâ€™s laboratory at the University of Minnesota, where he began research on immune system development in chickens.

In the early 1960s, Cooper explained, scientists thought that all immune cells developed in one place: the thymus. Working with Good, he showed that there are two lineages of immune cells in chickens: some that develop in the thymus (T cells) and other cells responsible for antibody production, which develop in the bursa of Fabricius (B cells). [On Thursday, he evoked chuckles by noting that a critical discovery that drove his work was published in the journal Poultry Science after being rejected by Science.]

Cooper moved on to the University of Alabama, Birmingham, and there made several discoveries related to how B cells develop. A collaboration with scientists at University College, London led to the identification of the places where B cells develop in mammals: fetal liver and adult bone marrow.

Cooperâ€™s research on lampreys began in Alabama and has continued after he came to Emory in 2008. Primitive lampreys are thought to be an early offshoot on the evolutionary tree, before sharks, the first place where an immune system resembling those of mammals and birds is seen. Lampreysâ€™ immune cells produce â€œvariable lymphocyte receptorsâ€ that act like our antibodies, but the molecules look very different in structure. These molecules were eventually crystallized and their structure probed, in collaboration with Ian Wilson in San Diego.

Lampreys have variable lymphocyte receptors, which resemble our antibodies in function but not in structure

Cooper said he set out to figure out â€œwhich came first, T cells or B cells?â€ but ended up discovering something even more profound. He found that lampreys also have two separate types of immune cells, and the finding suggests that the two-arm nature of the immune system may have preceded the appearance of the particular features that mark those cells in evolution.